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Genome-wide association study of hepatitis C virus- and cryoglobulin-related vasculitis

Abstract

The host genetic basis of mixed cryoglobulin vasculitis is not well understood and has not been studied in large cohorts. A genome-wide association study was conducted among 356 hepatitis C virus (HCV) RNA-positive individuals with cryoglobulin-related vasculitis and 447 ethnically matched, HCV RNA-positive controls. All cases had both serum cryoglobulins and a vasculitis syndrome. A total of 899 641 markers from the Illumina HumanOmni1-Quad chip were analyzed using logistic regression adjusted for sex, as well as genetically determined ancestry. Replication of select single-nucleotide polymorphisms (SNPs) was conducted using 91 cases and 180 controls, adjusting for sex and country of origin. The most significant associations were identified on chromosome 6 near the NOTCH4 and MHC class II genes. A genome-wide significant association was detected on chromosome 6 at SNP rs9461776 (odds ratio=2.16, P=1.16E−07) between HLA-DRB1 and DQA1: this association was further replicated in additional independent samples (meta-analysis P=7.1 × 10−9). A genome-wide significant association with cryoglobulin-related vasculitis was identified with SNPs near NOTCH4 and MHC Class II genes. The two regions are correlated and it is difficult to disentangle which gene is responsible for the association with mixed cryoglobulinemia vasculitis in this extended major histocompatibility complex region.

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Acknowledgements

This study was supported in part by research funding from Merck (to DLT and PD), through the National Institutes of Health, R01DA013324 (to DT) and the Office of AIDS Research. The REVELL study was funded by a grant from the National Heart, Lung and Blood Institute (R01HL076902). This work was supported in part by the National Institutes of Health (R01 AI060561 to LBD and K08AI075031 to EDC), Center for Translational Science Award (Pilot Grant CCL3001018; to EDC) and Center for Translational Science Award (Grant UL1 RR024143, to Rockefeller University), from the National Center for Research Resources, a component of National Institutes of Health. GML and AYK are supported by grants from the National Institutes of Health (DA033541, AI066345 and AI082630). The work was supported by a Wellcome Trust SCF Grant (WT076991MA) to SIK. The study was funded by AIRC (Associazione Italiana per la Ricerca sul Cancro), by ITT (Istituto Toscano Tumori) and by Fondazione Cassa di Risparmio di Firenze; Dr LG was supported by a fellowship from Fondazione Umberto Veronesi.

Author contributions

ALZ, PC, MV, MC, AM, EDC, LG, BT, VP, LBD, SIK, MPB, GML, AYK, LA and DLT collected data. DLT, GLW, PD and RL designed the research analysis and performed the statistical analysis. RL and DLT designed and performed the targeted genotyping. DLT, GLW, ALZ, LG and PD wrote the manuscript. All authors interpreted the data and revised the manuscript.

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Correspondence to P Duggal.

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P Cacoub is a board member at BMS, Boehringer Ingelheim, GSK, Gilead, Janssen, MSD, Roche, Servier and Vifor; he is a speaker for Astra Zeneca, BMS, Boehringer Ingelheim, GSK, Gilead, Janssen, MSD, Roche, Servier and Vifor; and he receives grants from BMS, GSK, Gilead, MSD, Roche, Servier and Vifor. The other authors declare no conflict of interest.

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Zignego, A., Wojcik, G., Cacoub, P. et al. Genome-wide association study of hepatitis C virus- and cryoglobulin-related vasculitis. Genes Immun 15, 500–505 (2014). https://doi.org/10.1038/gene.2014.41

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